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C8-Substituted Imidazotetrazine Analogs Overcome Temozolomide Resistance by Inducing DNA Adducts and DNA Damage.
by Yang Z, Wei D, Dai X, Stevens MFG, Bradshaw TD, Luo Y, Zhang J via pubmed: "front oncol"[jour]
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C8-Substituted Imidazotetrazine Analogs Overcome Temozolomide Resistance by Inducing DNA Adducts and DNA Damage.

Front Oncol. 2019;9:485

Authors: Yang Z, Wei D, Dai X, Stevens MFG, Bradshaw TD, Luo Y, Zhang J

Abstract
Temozolomide (TMZ) is the standard of care chemotherapeutic agent used in the treatment of glioblastoma multiforme. Cytotoxic O6-methylguaine lesions formed by TMZ are repaired by O6-methyl-guanine DNA methyltransferase (MGMT), a DNA repair protein that removes alkyl groups located at the O6-position of guanine. Response to TMZ requires low MGMT expression and functional mismatch repair. Resistance to TMZ conferred by MGMT, and tolerance to O6-methylguanine lesions conferred by deficient MMR severely limit TMZ clinical applications. Therefore, development of new TMZ derivatives that can overcome TMZ-resistance is urgent. In this study, we investigated the anti-tumor mechanism of action of two novel TMZ analogs: C8-imidazolyl (377) and C8-methylimidazole (465) tetrazines. We found that analogs 377 and 465 display good anticancer activity against MGMT-overexpressing glioma T98G and MMR deficient colorectal carcinoma HCT116 cell lines with IC50 value of 62.50, 44.23, 33.09, and 25.37 μM, respectively. Analogs induce cell cycle arrest at G2/M, DNA double strand break damage and apoptosis irrespective of MGMT and MMR status. It was established that analog 377, similar to TMZ, is able to ring-open and hydrolyze under physiological conditions, and its intermediate product is more stable than MTIC. Moreover, DNA adducts of 377 with calf thymus DNA were identified: N7-methylguanine, O6-methylguanine, N3-methyladenine, N3-methylthymine, and N3-methylcytidine deoxynucleotides. We conclude that C8 analogs of TMZ share a mechanism of action similar to TMZ and are able to methylate DNA generating O6-methylguanine adducts, but unlike TMZ are able at least in part to thwart MGMT- and MMR-mediated resistance.

PMID: 31263673 [PubMed]

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Transcriptional Activation of Gstp1 by MEK/ERK Signaling Confers Chemo-Resistance to Cisplatin in Lung Cancer Stem Cells.
by Li J, Ye T, Liu Y, Kong L, Sun Z, Liu D, Wang J, Xing HR via pubmed: "front oncol"[jour]
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Transcriptional Activation of Gstp1 by MEK/ERK Signaling Confers Chemo-Resistance to Cisplatin in Lung Cancer Stem Cells.

Front Oncol. 2019;9:476

Authors: Li J, Ye T, Liu Y, Kong L, Sun Z, Liu D, Wang J, Xing HR

Abstract
Lung cancer management remains a challenge due to its asymptomatic and late presentation when it is metastatic. The clinical response to the first-line platinum-based chemotherapy in patients with advanced lung cancer is disappointing due to the development of chemoresistance. Chemoresistance is a complex phenomenon. Mechanistic research using experimental models has yielded limited clinical results to help increase understanding for overcoming resistance. While the role of lung CSCs in conferring multidrug resistance has been postulated, experimental evidence remains associative and lacks in depth mechanistic inquisition. In the present study, using mouse and human lung adenocarcinoma cell lines and their respective paired CSC derivative cell lines that we generated, we identified cancer stem cell component of lung adenocarcinoma as the source that confers multidrug resistance phenotype. Mechanistically, Gstp1 confers cisplatin resistance in mouse and human lung CSC models, both in vitro and in vivo. Further, transcriptional activation of Gstp1 expression by MEK/ERK signaling underlies cisplatin resistance in lung CSC cells. Moreover, we show that GSTP1 expression is a poor diagnostic and prognostic marker for human lung adenocarcinoma, thus is of high clinical relevance. Taken together, we have provided mechanistic understanding of the lung CSC in mediating chemoresistance.

PMID: 31263672 [PubMed]

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Utility of Immunophenotypic Measurable Residual Disease in Adult Acute Myeloid Leukemia-Real-World Context.
by Patkar N, Kakirde C, Bhanshe P, Joshi S, Chaudhary S, Badrinath Y, Ghoghale S, Deshpande N, Kadechkar S, Chatterjee G, Kannan S, Shetty D, Gokarn A, Punatkar S, Bonda A, Nayak L, Jain H, Bagal B, Menon H, Sengar M, Khizer SH, Khattry N, Tembhare P, Gujral S, Subramanian P via pubmed: "front oncol"[jour]
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Utility of Immunophenotypic Measurable Residual Disease in Adult Acute Myeloid Leukemia-Real-World Context.

Front Oncol. 2019;9:450

Authors: Patkar N, Kakirde C, Bhanshe P, Joshi S, Chaudhary S, Badrinath Y, Ghoghale S, Deshpande N, Kadechkar S, Chatterjee G, Kannan S, Shetty D, Gokarn A, Punatkar S, Bonda A, Nayak L, Jain H, Bagal B, Menon H, Sengar M, Khizer SH, Khattry N, Tembhare P, Gujral S, Subramanian P

Abstract
Introduction: One of the mainstays of chemotherapy in acute myeloid leukemia (AML) is induction with a goal to achieve morphological complete remission (CR). However, not all patients by this remission criterion achieve long-term remission and a subset relapse. This relapse is explained by the presence of measurable residual disease (MRD). Methods: We accrued 451 consecutive patients of adult AML (from March 2012 to December 2017) after informed consent. All patients received standard chemotherapy. MRD testing was done at post-induction and, if feasible, post-consolidation using 8- and later 10-color FCM. Analysis of MRD was done using a combination of difference from normal and leukemia-associated immunophenotype approaches. Conventional karyotyping and FISH were done as per standard recommendations, and patients were classified into favorable, intermediate, and poor cytogenetic risk groups. The presence of FLT3-ITD, NPM1, and CEBPA mutations was detected by a fragment length analysis-based assay. Results: As compared to Western data, our cohort of patients was younger with a median age of 35 years. There were 62 induction deaths in this cohort (13.7%), and 77 patients (17.1%) were not in morphological remission. The median follow-up was 26.0 months. Poor-risk cytogenetics and the presence of FLT3-ITD were significantly associated with inferior outcome. The presence of post-induction MRD assessment was significantly associated with adverse outcome with respect to OS (p = 0.01) as well as RFS (p = 0.004). Among established genetic subgroups, detection of MRD in intermediate cytogenetic and NPM1 mutated groups was also highly predictive of inferior outcome. On multivariate analysis, immunophenotypic MRD at the end of induction and FLT3-ITD emerged as independent prognostic factors predictive for outcome. Conclusion: This is the first data from a resource-constrained real-world setting demonstrating the utility of AML MRD as well as long-term outcome of AML. Our data is in agreement with other studies that determination of MRD is extremely important in predicting outcome. AML MRD is a very useful guide for guiding post-remission strategies in AML and should be incorporated into routine treatment algorithms.

PMID: 31263671 [PubMed]

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